Diabetes mellitus (DM) is a leading cause of morbidity, mortality, and economic cost. Conventional treatment with insulin injections and diet has not prevented or reversed the debilitating secondary complications of insulin-dependent DM (IDDM), presumably because of imperfect control of metabolic abnormalities such as hyperglycemia. There is justifiable interest, therefore, in pancreas transplantation (PT) and other forms of endocrine pancreas replacement therapy (ERPT) that might provide precise metabolic control and prevent, stabilize and reverse complications of DM. Over 1500 patients have undergone PT, yet it is not known if PT or any form of EPRT can reverse or stabilize established pathologic lesions of IDDM. The fact is that no quantitative morphologic studies of diabetic lesions have been done in human transplant recipients, probably because of the high risks and many years of observation that such studies entail. Therefore, it is essential that the validity of PT be assessed in animal models with DM that is similar to human IDDM. One such animal model is the alloxan diabetic rat in which we and many others have documented severe nephropathy, neuropathy, eye lesions, cardiovascular lesions, gonadal lesions, and microangiopathy that are strikingly similar to the lesions found in human IDDM. Can PT and other forms of EPRT reverse or, at least, stabilize established pathologic lesions of IDDM? To answer this crucial question, we have done extensive preparatory work in which we treated approximately 1000 highly inbred rats with severe alloxan IDDM by syngeneic whole PT at 6, 9, 12, 15, 18, and 21 months after onset of DM. The rats had extensive metabolic studies and were sacrificed monthly for 2 years to provide a large and unique bank of tissues for histopathologic studies. Our results to date have documented that whole PT provides precise metabolic control, prevents nephropathy and neuropathy and, for the first time, reverses mesangial enlargement and somatic neuropathy. Since there is no evidence that the various lesions of IDDM share a common pathogenesis or behavior, the current grant proposal is designed to complete this important project, using objective, quantitative morphometric methods to determine if important project, using objective, quantitative morphometric methods to determine if whole PT has reversed or halted the progression of the other established diabetic lesions in the kidney, nerves, eye, cardiovascular system, and microvasculature. The results of these studies are likely to be applicable to patients with IDDM.